Thursday, November 21, 2024
11/21/2024
Optimal cellular function requires balanced networks that maintain a proper flux of protein synthesis, folding, trafficking, remodeling and degradation. There are many conserved and abundant multi-component enzyme complexes that directly support this balance across eukaryotic life and are therefore critical control points for maintaining proteostasis. During the project period, we propose to achieve three major goals, each of which addresses an important, yet distinct, component of proteostasis: first, we will determine how the Cdc48 AAA+ ATPase resolves translational stress by working with the Ribosome Quality Control complex to remove stalled products of translation; second, we aim to determine the mechanisms of how the CCT chaperone machine facilitates the co-translational folding of native protein substrates; and third, we will determine how Cdc48 works with multiple adaptor proteins to facilitate protein unfolding prior to their targeted degradation. Each of these complexes are critical to maintaining cellular health, and their misregulation directly causes a variety of degenerative phenotypes. In order to meet our proposed goals, my lab will employ an integrative, “lysate-to- grid” approach that combines endogenous purifications, proteomics, cryo-EM imaging, and computational processing to visualize the mechanisms of protein quality control machinery in their functional states. This approach will enable us to understand the atomic-scale details of the continuous motions that underlie the fundamental cellular processes of protein synthesis, folding, and unfolding, including how incomplete products of translation are extracted from stalled ribosomes, how chaperones fold proteins as they are translated, and how folded proteins overcome their energetic barriers to become unfolded prior to their degradation. Overall, the insights we uncover will deepen understanding of how cells maintain proteostasis and how disruptions in protein quality control machinery contribute to cellular dysfunction.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
